Compositions containing platinum

ABSTRACT

This invention relates to a compound of platinum having the structure: ##STR1## in which X and Y are halogenoid groups which are the same or different and are preferably both chloride but may be other halide or pseudohalide such as cyanate, thiocyanate and azide or other similar groups, and A and B are the same or different branched chain aliphatic amine groups co-ordinated to the Pt through their N atoms.

This invention relates to new compositions of matter containing platinum.

According to one aspect of the present invention a composition of matter comprises a co-ordination compound of platinum having the structure: ##STR2## in which X and Y are halogenoid groups which are the same or different and are preferably both chloride but may be other halide or pseudohalide such as cyanate, thiocyanate and azide and A and B are the same or different branched chain aliphatic amine groups co-ordinated to the Pt through their N atoms.

According to a second aspect of the present invention there is provided a co-ordination compound of platinum having the structure: ##STR3## in which X and Y are halogenoid groups which are the same or different and are preferably both chloride but may be other halide pseudohalide such as cyanide, cyanate, thiocyanate, or azide or other similar groups and A and B are the same or different branched chain aliphatic amine groups or C-substituted branched chain aliphatic amine groups co-ordinated to the Pt through their N atoms each having the general formula

    C.sub.n R.sub.2n+1 NH.sub.2

in which n may vary from 3 to 9 and in which all of the R groups are either the same or different and are preferably all hydrogen but may be selected from the group consisting of hydrogen, alkyl, aryl, alkaryl, aralkyl, halogen, pseudohalogen, hydroxy, carbonyl, formyl, nitro, amido, amino, sulphonic acid, sulphonic acid salt, carboxylic acid, carboxylic acid salt, and substituted alkyl, aryl, alkaryl and aralkyl groups.

The platinum is preferably present as Pt⁴⁺, thus producing a neutral complex with two hydroxyl and two halide ligands.

Although R groups other than hydrogen are not normally preferred, they may be used and may comprise lower alkyl such as methyl or ethyl or a solubilizing group such as a sulphonic acid group. Solubilizing groups as substituents such as carboxylic acid, sulphonic acid, carboxylic acid salt, sulphonic acid salt, e.g. the sodium, potassium or lithium salts are sometimes appropriate when the clinical conditions require high solubility.

Throughout the specification and claims, the term "halogenoid" is used to mean halide (chloride, bromide, iodide or fluoride) or pseudohalide such as cyanide, cyanate, thiocyanate or azide.

Suitable branched chain amine compounds which may be used for groups A and B are isopropylamine, isobutylamine, isoamylamine and 2-aminohexane.

Results obtained using trans di-hydroxo complexes of Pt(IV) where in the above formula X and Y are both chloride and A and B are the same stated branched chain amine are as follows:

    ______________________________________                                                         mgm./Kgm  Therapeutic                                          Tumour   A and B      ID.sub.90                                                                              LD.sub.50                                                                            Index (II)                                 ______________________________________                                         ADJ/PC6  exo 2 amino nor                                                                             40.5    660   16.3                                                bornane                                                                        ISO propylamine                                                                             7.5     90    12.0                                                (oil)                                                                          (water)      4.2     54    12.9                                                ISO Butylamine                                                                              19.5    410   21                                                  ISO pentylamine                                                                             112     800   7.1                                                 (amylamine)  19.0    20    37.9                                       ______________________________________                                                               ED.sub.90                                                                              LD.sub.50                                                                            TI                                         ______________________________________                                         Walker   ISO propylamine                                                                (oil)        17      45    2.6                                                 (water)      16      56    3.5                                        ______________________________________                                    

These results were obtained using the standard test protocol for the ADJ/PC6 and Walker tumours on Balb-c white mice.

These series of results obtained using the standard test protocol for the P 388 (ascitic) lymphocytic leukaemia using the isopropylamine complex are as follows:

    ______________________________________                                                                                 % age                                        Control  Animal                   Increase                               Dose  Body     weight    Tumour  Control                                                                               in life                                mgm/  weight   difference                                                                               evaluation                                                                             (Days) span                                   Kgm   change   (T - C)   Test (days)                                                                            (C)    (T/C)                                  ______________________________________                                         200   -1.4     -4.6      6.2     15.5                                          100   -1.4     -4.0      6.4     15.5                                          50.0  -1.4     -3.6      24.0    15.5   154                                    25.0  -1.4     -1.6      23.3    15.5   150                                    12.5  -1.4     -1.8      21.3    15.5   137                                    200   1.0      -1.0      4.19    11.8                                          100   1.0      -6.4      6.1     11.8                                          50.0  1.0      -6.5      8.0     11.8                                          25.0  1.0      -5.7      15.0    11.8   127                                    12.5  1.0      -4.2      21.8    11.8   184                                    200   1.0      -1.0      3.0     11.8                                          100   1.0      -6.5      6.8     11.8                                          50.0  1.0      -5.2      18.0    11.8   152                                    25.0  1.0      -4.0      16.1    11.8   136                                    12.5  1.0      -2.5      15.3    11.8   129                                    ______________________________________                                    

Other branched chain amines which may be used as ligands A and B are:

2 amino 5 methylhexane

2 amine 4 methylhexane

2 amino heptane

tert. butylamine

Methods of Preparation

Preferred methods of preparation of trans dihydroxo cis dichloro diamine Pt (IV) complexes (i.e. where A+B in the above defined structure are as follows:

The complexes are prepared by the general method of heating a slurry of the respective cis-diaminedichloroplatinum (II) complex with hydrogen peroxide solution as exemplified below.

Preparation of cis-Dichloro-trans-dihydroxybis(Isopropylamine) platinum IV hydrate (1/1)

Recrystallised cis- [Pt(i-C₃ H₇ NH₂)₂ Cl₂ ] (26.8 g) was slurried in hot water (50 ml) and aqueous hydrogen peroxide (40% v/v, 100 ml) was added with stirring. The slurry was boiled for 0.5 hours until yellow in colour, chilled, filtered and the residue washed with water, etharal and air dried. The crude product (20 g) was recrystallised from water (285 ml) with hydrogen peroxide solution (15 ml) and dried in vacuo at 100° C. for four hours.

Yield 10.5 g. 35%

    ______________________________________                                         Elemental analysis                                                                         C        H       N     O     Cl                                    ______________________________________                                         Calculated %                                                                               16.5     5.1     6.4   11.-  16.3                                  Found %     16.6     4.8     6.4   11.7  16.1                                  ______________________________________                                    

Infra-red spectrum

The hydroxyl stretching absorption (v_(o) --H) occurs at 3515 m cm⁻¹

Preparation of cis-bis(2-amino-5-methylhexane)dichloro-trans dihydroxy platinum (IV)

Recrystallised cis- [Pt(C₇ H₁₅ NH₂)₂ Cl₂ ] (15 g) was slurried in warm water (31 ml) and hydrogen peroxide solution (40% v/v,60 ml) was added with stirring. The slurry was boiled for ten minutes, chilled, filtered and the orange product washed with water and dried in vacuo.

Yield 7.4 g. 46%

    ______________________________________                                         Elemental analysis                                                                         C        H       N     O     Cl                                    ______________________________________                                         Calculated %                                                                               31.7     6.8     5.3   6.0   13.4                                  Found %     32.1     6.7     5.5   6.2   13.6                                  ______________________________________                                    

Infra-red Spectrum

The hydroxyl stretching absorption (v_(o) --H) occurs at 3340 mg cm⁻¹.

Platinum (IV) complexes are more soluble than Platinum (IV) complexes are more soluble than platinum (II) complexes and, after solubilizing Pt(IV) may be used in the form of Pt(II). The branched chain amine complexes of Pt(IV) are also useful in catalyst preparation by impregnating supports with an aqueous solution of the complex. Alternatively, the solution may be based upon an organic medium. The complexes of the invention may also be used as catalysts in the hydrosilation of organic compounds so as to introduce a silica radical into an organic compound and as synthetic intermediate compounds. 

What is claimed is:
 1. A co-ordination compound of platinum having the structure: ##STR4## in which X and Y are halogen and A and B are the same or different branched chain aliphatic amine groups or C-substituted branched chain aliphatic amine groups co-ordinated to the Pt through their N atoms each having the general formula

    C.sub.n R.sub.2n+1 NH.sub.2

in which n may vary from 3 to 9 and in which all of the R groups are the same or different and are selected from the group consisting of hydrogen, alkyl, aryl, alkaryl, aralkyl, halogen, pseudohalogen, hydroxy, carbonyl, formyl, nitro, amido, amino, sulphonic acid, sulphonic acid salt, carboxylic acid and carboxylic acid salt.
 2. A compound according to claim 1 in which X and Y are both chlorine and R is hydrogen.
 3. A compound according to claim 1 wherein the platinum is present as Pt⁴⁺.
 4. A compound according to claim 1 wherein the R groups are the same or different lower alkyl.
 5. A compound according to claim 1 wherein A and B are isopropylamine, isobutylamine, isoamylamine and 2-aminohexane.
 6. A composition comprising a co-ordination compound of platinum having the structures: ##STR5## in which X and Y are halogen and A and B are exo 2 amino norbornane. .Iadd.
 7. The compound cis-dichloro-trans-dihydroxybis (isopropylamine) platinum IV hydrate. .Iaddend..Iadd.
 8. A compound according to claim 1 wherein X and Y are both chlorine and A and B are both isopropylamine. .Iaddend. 